Project Summary/Abstract Up to twenty percent of individuals living at high altitude in the Peruvian mountains and, to a lesser degree in Tibet, suffer from Monge's disease or Chronic Mountain Sickness (CMS). These subjects die in early adulthood because of excessive erythrocytosis (Polycythemia, hematocrit>60%). It is estimated that there are over 100 million people who live at altitudes > 2500 m world-wide, who are at risk for CMS. We are particularly interested in patients with CMS because they constitute a unique population that allows us to study how mechanisms of erythropoiesis can become awry or get exaggerated based on environmental conditions. The uniqueness of this population is even more significant when we realize that there are subjects that live side by side at similar altitudes as those with CMS but do not suffer from this disease. We have already demonstrated through whole genome sequencing that there are several genome-wide regions (containing a number of genes) that are consistent with selective sweeps in Peruvian subjects with polycythemia. Further, with the use of skin biopsies and native blood cells from CMS and non-CMS subjects, we have obtained iPS cells and differentiated them into red blood cells. We will use in this application the results of our already analyzed whole genomes of >100 CMS and non-CMS subjects as well as other molecular and genomic tools to better understand the role of SENP1 in hypoxia and understand the mechanistic basis of protection in females. Based on our preliminary results, we have formulated the central hypothesis that the hypoxia-induced polycythemia of high altitude has a genetic basis and that SENP1 plays a critical role in this extreme trait of polycythemia in Monge's disease. Our Specific Aims are: Specific Aim 1: Elucidate the role of SENP1 single nucleotide polymorphisms (SNPs) in regulating the marked hypoxia-induced polycythemia in CMS and the lack thereof in non-CMS subjects. We hypothesize that specific SNPs regulate SENP1 up-regulation in CMS but not in non-CMS in response to hypoxia. Specific Aim 2: Determine the transcriptomic changes and pathways that play an important role in the hypoxia-induced polycythemia in CMS. We hypothesize that an up-regulation of SENP1 will induce specific transcriptional changes in CMS cells that lead to the CMS polycythemic phenotype. Specific Aim 3: Investigate the role of hormonal factors in the gender-dependent high altitude induced excessive erythropoiesis. We hypothesize that the effect of estrogen hormone on SENP1/GATA1 is responsible for protection of females from CMS polycythemia.